JPH0465834B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to phthalidyl ammonium derivatives. More specifically, it relates to a phthalidyl ammonium derivative represented by the following general formula (). (In the formula, X represents halogen, trihalogenoacetyloxy, alkylsulfonyloxy, or arylsulfonyloxy, R ¹ , R ² and R ³ each represent alkyl, or R ¹ is alkyl and R ² and R ³ are (represents a 5- or 6-membered ring which may contain oxygen together with adjacent nitrogen atoms, R ⁴ and R ⁵ each represent hydrogen) Phthalidyl ammonium derivative provided by the present invention, 1-phthalidyl represented by the general formula () -5
- Can be used as a raw material in the production of fluorouracil derivatives. (In the formula, R ⁴ and R ⁵ have the same meanings as above.) The 1-phthalidyl-5-fluorouradyl derivative obtained using the compound of the present invention has excellent antitumor activity, especially in the uterus. cancer, cafeteria cancer, skin cancer,
Stomach cancer, lung cancer, liver cancer, colon, rectal cancer, pancreatic cancer, breast cancer, bladder cancer, chorionic tumor, brain tumor, lymphosarcoma,
It is a useful compound that is effective in treating malignant tumors such as leukemia and preventing metastasis. [Unexamined Japanese Patent Publication No. 1987-
16881, Japanese Patent Application Laid-open No. 57-67578, etc. ]
The present inventors have completed the present invention as a result of intensive research aimed at improving the manufacturing method of 1-phthalidyl-5-fluorouracil derivatives. In the above definition, halogen means fluoro, chloro, bromo, and iodo, and trihalogenoacetyloxy means trifluoroacetyloxy, trichloroacetyloxy, tribromoacetyloxy, and the like. Alkylsulfonyloxy is an alkylsulfonyloxy having 1 to 5 carbon atoms, such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,
These include isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, t-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, t-pentylsulfonyloxy, and the like. Arylsulfonyloxy means benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, p-chlorobenzenesulfonyloxy, p-
It means methoxybenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, etc. Alkyl is an alkyl having 1 to 5 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl,
These are isobutyl, pentyl, and isopentyl. The 5- or 6-membered ring which may contain oxygen together with adjacent nitrogen atoms means pyrrolidino, piperidino, morpholino and the like. The compound () of the present invention can be easily produced by reacting a compound represented by the following general formula () with a tertiary base represented by the general formula ().

【formula】

[Formula] (In the formula, X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as above.) As the tertiary base represented by the general formula ( Examples include -n-propylamine, tri-n-butylamine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholine, and quinuclidine. Further, the compound represented by the general formula () is a commercially available product or can be easily produced by a known method described in literature.
[For example, JP-A-57-16881] The above reaction is carried out in a suitable solvent at room temperature or under heating, and takes several hours to several days to complete the reaction. The solvent may be appropriately selected from aprotic solvents such as dichloromethane, benzene, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. Further, these reactions may be accelerated by adding a catalytic amount of a suitable sodium halide, potassium halide, or tetraalkylammonium halide. The compound of the present invention can also be converted from a compound in which X represents halogen in the general formula () to a compound in which X represents trihalogenoacetyloxy, alkylsulfonyloxy, or arylsulfonyloxy by reaction with a corresponding silver salt. be able to. The reaction is carried out in a suitable solvent at room temperature and takes several hours to several days to complete.
Solvents are acetonitrile, tetrahydrofuran,
dimethylformamide, dimethylacetamide,
The solvent may be appropriately selected from aprotic solvents such as dimethyl sulfoxide, but acetonitrile is preferably used. Using the compound of the present invention, 1-phthalidyl-5
- To produce a fluorouracil derivative, a compound of the invention and 5-
Fluorouracil (hereinafter abbreviated as 5-FU) is reacted at room temperature. The reaction is complete in a few hours. The solvent may be appropriately selected from aprotic solvents such as acetonitrile, tetrahydrofuran, dimethylformamide, dimethylastamide, and dimethylsulfoxide, but it is preferable to use dimethylformamide or dimethylsulfoxide. As the base, organic bases such as triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, picoline, collidine, and dimethylaniline, and inorganic bases such as potassium carbonate and sodium carbonate can be used, but preferably Use triethylamine. The advantage of the above method using the compound of the present invention as a starting material compared with the method described in JP-A-57-16881 using 3-halogenophthalide as a starting material is that according to the above method, N( 1) - Substitution -
5-FU was obtained selectively and in good yield, N(1),
The by-product of N(3)-disubstituted-5-FU is hardly observed. The compound of the present invention can also be used as a raw material for talampicillin represented by the following formula. Examples and reference examples are shown below to clarify aspects of the present invention. Example 1 Bromide/N,N,N-triethyl-3-oxo-
Production of 1,3-dihydro-1-isobenzofuranylammonium 8.52 g (40 mmol) of 3-bromo-1,3-dihydro- 1 -isobenzofuranone 1 and 27.87 ml (200 mmol) of triethylamine were reacted in 85 ml of tetrahydrofuran at room temperature for 96 hours, and after filtering out the precipitated crystals. and washing with dichloromethane to obtain 11.04 g (yield 88%) of the title compound 2 . Melting point 173-174℃ NMR: δ ^d ₆ ^DMSO 1.25 (t, J = 8.0Hz, 9H), 3.58
(q, J=8.0Hz, 6H), 7.16 (s, 1H), 7.80~
8.23 (m, 4H) Elemental analysis (as C ₁₄ H ₂₀ NO ₂ Br): Calculated value: C, 53.51; H, 6.42; N, 4.46 Experimental value: C, 53.07; H, 6.42; N, 4.52 Example 2 Bromide/4-methyl-4-(3-oxo-1,3
Production of -dihydro-1-isobenzofuranyl)-morpholinium 5.34 g (25 mmol) of 3-bromo-1,3-dihydro-1-isobenzofuranone 1 and 2.75 ml (25 mmol) of N-methylmorpholine were dissolved in benzene 20
ml at room temperature for 70 hours, filter out the precipitated crystals, and wash with benzene to obtain 6.52 g of the title compound 3.
(yield 83%). Melting point - (decomposition) 198-200℃ NMR: δ ^d _6DMSO 30.3 (s, 3H), 3.4-4.2 (m,
8H), 7.33 (s, 1H), 7.8-8.3 (m, 4H) Example 3 Chloride/N,N,N-triethyl-3-oxo-
Production of 1,3-dihydro-1-isobenzofuranylammonium 5.05 g (30 mmol) of 3-chloro-1,3-dihydro-1-isobenzofuranone 4 , 12.5 ml (90 mmol) of triethylamine, and 225 mg (1.5 mmol) of sodium iodide are mixed in 20 ml of acetonitrile.
The mixture was stirred and reacted for 7 hours under heating under reflux. After distilling off the solvent and excess triethylamine under reduced pressure, dichloromethane is added to the residue and the precipitated crystals are collected to obtain crude crystals of the title compound 5 . NMR: δ ^d _6DMSO 1.24 (t, J = 8.5Hz, 9H), 3.59
(q, J=8.5Hz, 6H), 7.23 (s, 1H), 7.80~
8.27 (m, 4H) Example 4 Preparation of 4-methyl-4-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-morpholinium chloride The title compound 6 is obtained in the same manner as in Example 2. NMR: δ ^d ₆ ^DMSO 30.3 (s, 3H), 3.7-4.2 (m,
8H), 7.43 (s, 1H), 7.9-8.25 (m, 4H). Example 5 N,N,N-triethyl-3-oxo-1,3
-Production of dihydro-1-isobenzofuranylammonium trifluoroacetate Bromide/N,N,N-triethyl-3-oxo-
4.0 g (12.7 mmol) of 1,3-dihydro-1-isobenzofuranylammonium 2 and 2.81 g (12.7 mmol) of silver trifluoroacetate were reacted in acetonitrile at room temperature for 63 hours, and then the solvent was distilled off under reduced pressure. The resulting residue was filtered with dichloromethane to remove silver bromide, and the resulting solution was concentrated under reduced pressure to obtain the title compound 7 . NMR: δ ^d ₆ ^DMSO 1.23 (t, J = 8.0Hz, 9H), 3.56
(q, J=8.0Hz, 6H), 7.07 (s, 1H), 7.80~
8.27 (m, 4H). Example 6 N,N,N-triethyl-3-oxo-1,3
-Production of dihydro-1-isobenzofuranylammonium methanesulfonate Bromide/N,N,N-triethyl-3-oxo-
2.13 g (6.78 mmol) of 1,3-dihydro-1-isobenzofuranylammonium 2 and 1.38 g (6.78 mmol) of silver methanesulfonate were allowed to react in acetonitrile for 15 hours, and then the solvent was distilled off under reduced pressure. The resulting residue was filtered with dichloromethane to remove silver bromide, and the resulting solution was concentrated under reduced pressure to obtain the title compound 8 . NMR: δ ^d ₆ ^DMSO 1.23 (t, J = 8.0Hz, 9H), 2.30
(s, 3H), 3.55 (q, J=8.0Hz, 6H), 7.03
(s, 1H), 7.80-8.25 (m, 4H). Example 7 N,N,N-triethyl-3-oxo-1,3
-Production of dihydro-1-isobenzofuranylammonium p-toluenesulfonate Bromide/N,N,N-triethyl-3-oxo-
1.87 g (5.95 mmol) of 1,3-dihydro-1-isobenzofuranylammonium 2 and 1.62 g (5.95 mmol) of silver p-toluenesulfonate were reacted in acetonitrile for 15 hours, and then the solvent was distilled off under reduced pressure. Silver bromide was removed by adding dichloromethane to the obtained residue and filtering it, and the obtained liquid was concentrated under reduced pressure to obtain the title compound 9 . NMR: δ ^d ₆ ^DMSO 1.22 (t, J=8.0Hz, 9H), 2.27
(s, 3H), 3.53 (q, J=8.0Hz, 6H), 7.00
(s, 1H), 7.10. (d, J=8.0Hz, 2H), 7.50
(d, J=8.0Hz, 2H), 7.80-8.23 (m, 4H). Example 8 Bromide/4-ethyl-4-(3-oxo-1,3
Production of -dihydro-1-cysobenzofuranyl)-morpholinium 2.13 g (10 mmol) of 3-bromo-1,3-dihydro-1-isobenzofuranone 1 and 1.27 ml (10 mmol) of N-ethylmorpholine are dissolved in 21 ml of acetonitrile and reacted under heating under reflux for 3 hours. Precipitation occurs after cooling. The crystals are collected and washed with ether to obtain 2.36 g (yield 72%) of the title compound 10. Melting point (decomposition) 163-168°C NMR: δ ^d ₆ ^DMSO 1.21 (t, J = 7 Hz, 3H), 3.5～
4.2 (m, 10H), 7.30 (s, 1H) 7.83-8.30 (m,
4H) Reference Example 1 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 3.14 g (10 mmol) of Compound 2 obtained in Example 1 was dissolved in 26 ml of anhydrous dimethylformamide along with 1.3 g (10 mmol) of 5-FU, and 0.14 ml (1 mmol) of triethylamine was added and reacted at room temperature for 15 hours. After that, the reaction solution was poured into ice water containing 5 ml of 2N hydrochloric acid.
Pour into 260ml and stir for 30 minutes. By collecting the precipitated crystals, 2.44 g of the title compound 11 (yield: 93
%). This is recrystallized from dimethyl sulfoxide water to obtain white crystals with a melting point of 290°C or higher. Elemental analysis (as C ₁₂ H ₇ O ₄ N ₂ F): Calculated: C, 54.97; H, 2.69; N, 10.69; F,
7.24 Experimental value: C, 54.95; H, 2.77; N, 10.38; F,
7.64 IR: ν ^KBr _nax 1798, 1715, 1686, 1670 cm ^-1 . UV: λ ^EtOH _nax (ε) 227 (17400), 264 (10000). NMR: δ ^d ₆ ^DMSO 4.36 (broad, 1H), 7.5-8.2 (m,
4H), 7.56 (s, 1H), 7.67 (d, J=7Hz,
1H). Reference Example 2 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 3.48 g (26.7 mmol) of 5-FU, 8.40 g (26.7 mmol) of compound 3 obtained in Example 2, and 3.69 g (26.7 mmol) of anhydrous potassium carbonate were added to 35 ml of dimethyl sulfoxide, and the mixture was stirred well at room temperature for 15 hours. Make it react. After pouring the reaction solution into about 350 ml of ice water containing 27 ml of 2N hydrochloric acid and stirring for about 15 minutes,
The precipitated crystals are collected, washed three times with 30 ml of water, once with 30 ml of methanol, and once with 30 ml of ether, and then dried to obtain 6.56 g (yield: 94.0%) of the title compound 11 . Reference Example 3 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil 927 mg (7.13 mmol) of 5-FU and 1 molar equivalent of compound 5 obtained in Example 3 were dissolved in 6 ml of anhydrous dimethyl sulfoxide, and 0.5 mg of triethylamine was dissolved.
ml (3.6 mmol) and reacted at room temperature for 15 hours. The reaction solution was then poured into 100 ml of ice water containing 5 ml of 2N hydrochloric acid and stirred for 30 minutes. By collecting the precipitated crystals, 1.76 g (yield 94%) of the title compound 11 is obtained. Reference Example 4 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil In the same manner as in Reference Example 2, the compound 6 obtained in Example 4 is reacted with 5-FU in dimethyl sulfoxide in the presence of 1 molar equivalent of anhydrous potassium carbonate at room temperature to give the title compound 11 in good yield. obtain. Reference Example 5 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil Compound 7 obtained in Example 5 was dissolved in 32 ml of anhydrous dimethylformamide together with 1.66 g (12.7 mmol) of 5-FU without purification, and 0.18 ml (1.27 mmol) of triethylamine was added and allowed to react at room temperature for 15 hours. Pour the solution into ice water containing 7 ml of 2N hydrochloric acid.
Pour into 320ml and stir for 30 minutes. By collecting the precipitated crystals, 3.16 g of the title compound 11 (yield: 95
%). Reference Example 6 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil Compound 8 obtained in Example 6 was dissolved in 16 ml of anhydrous dimethylformamide together with 0.881 g (678 mmol) of 5-FU without purification, and 94 μm (0.678 mmol) of triethylamine was added and reacted at room temperature for 15 hours. Ice water containing 4 ml of 2N hydrochloric acid
Pour into 160ml and stir for 30 minutes. By collecting the precipitated crystals, 1.68 g of the title compound 11 (yield
95%). Reference Example 7 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil Compound 9 obtained in Example 7 was dissolved in 14 ml of anhydrous dimethylformamide along with 0.774 g (5.95 mmol) of 5-FU without purification, and 83 μm (0.60 mmol) of triethylamine was added and reacted at room temperature for 15 hours. Ice water containing 3 ml of 2N hydrochloric acid
Pour into 140ml and stir for 30 minutes. By collecting the precipitated crystals, 1.50 g of the title compound 11 (yield 96
%). Reference Example 8 Production of 1-(3-oxo-1,3-dihydro-1-isobenzofuranyl)-5-fluorouracil In the same manner as in Reference Example 2, the compound 10 obtained in Example 8 is reacted with 5-FU in dimethyl sulfoxide in the presence of 1 molar equivalent of anhydrous potassium carbonate at room temperature to give the title compound 11 in good yield. obtain.

Claims (1)

[Claims] 1. General formula: (In the formula, X represents halogen, trihalogenoacetyloxy, alkylsulfonyloxy, or arylsulfonyloxy, and R ¹ , R ² and R ³
each represents alkyl, R ¹ is alkyl, R ² and R ³ represent a 5- or 6-membered ring which may contain oxygen together with the adjacent nitrogen atom, and R ⁴ and R ⁵ each represent hydrogen) compound.